Throughout this application, various references are identified by authors and full citation. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The present invention relates to novel aminoindene derivatives, their preparation and their use to treat neurodegenerative conditions such as Alzheimer""s disease, idiopathic-, accident-, and drug-induced seizures, and to treat acute neurological traumatic disorders such as head trauma, stroke, hypoxia/anoxia. More specifically, the invention describes aminoindene derivatives of structure 1, wherein n is 1 or 2, R1 is hydrogen or lower alkyl or lower alkoxy and R2 is hydrogen or a halogen, having useful neuroprotective and anti-convulsant properties. These compounds will also be useful as adjunct therapy in the above conditions. 
The relevant art reveals several aminoindans. See for example, Youdim, et al., (U.S. Pat. No. 5,599,991), Guillaumet et al., (U.S. Pat. No. 5,569,669), and Oshiro et al., (U.S. Pat. No. 4,788,130). Cohen, et al., International Application published under PCT, Publication No. WO 95/18617, disclosed that 1-aminoindan derivatives have anticonvulsant and other activity in the central nervous system.
One such 1-aminoindan derivative, N-acetyl-1-aminoindan (structure 2), has strong anticonvulsant activity with the R-enantiomer (structure 2a) showing somewhat greater activity than the S-isomer. This result was observed in the Maximal Electroshock Model (MES) representing general and partial seizures, and in the subcutaneous pentylenetetrazol seizure threshold test (scMET) model (mice only) representing absence seizures. However, these stereoisomers afforded only modest protection against hypobaric hypoxia in mice. 
While 1-aminoindan derivatives have been well-studied, the structure and pharmacologic activity of aminoindenes remain practically unexplored. Brettle and Mosedale (J. Chem. Soc., Perkin Trans. I, 1988, 2187-95) have noted that some highly complex secondary enamides occur in nature but have not disclosed any uses of enamides.
Barton et al., Tetrahedron Letters (1988) 29: 3343-3346, prepared an analog of structure 1 where n is 2, and R1 and R2 are hydrogen, but solely as an intermediate in a synthesis leading to vinyl isonitriles, with no disclosure of any pharmacological studies.
Similarly, Zheng et al., Tetrahedron Letters, (1997) 38: 2817-2820, prepared an analog of structure 1 where n is 1, R1 is isobutyl and R2 is hydrogen. Zheng et al., obtained that compound as a minor by-product and have not explored its pharmacological activity.
In contrast to the above-described work by other investigators, the present invention discloses not only novel N-acylaminoindenes (also known as indenamides) and their synthesis, but also methods of using the N-acylaminoindenes as neuroprotectants and anticonvulsants.
As a class, the present compounds are novel, achiral with respect to the species having a five-membered ring and a more planar configuration than structure 2. One would expect that the presently disclosed aminoindene derivatives, which are achiral, would be less active than compound 2a as anticonvulsants and neuroprotectants because normally the hypothetical enzymatic or cellular active site interacting with these compounds prefers a chiral molecule. Surprisingly, the presently disclosed aminoindenes which are achiral, have shown significant anticonvulsant and neuroprotectant properties. In particular, they are anticonvulsant to about the same degree as compound 2 in the MES and scMET models described above. More significantly, they display very pronounced neuroprotective action in the hypobaric hypoxia model. They are also more effective than compound 2 in depressing response to both electrical and chemical stimulation in a guinea pig ileal preparation, and in potentiating the effect of exogenous adenosine. All this activity indicates unexpected but significant neuroprotection.
The present compounds which have been found to have neuroprotective properties are useful in neuroprotection after deprivation impact events such as trauma, stroke, and hypoxia/anoxia. The present compounds have also been found to have anticonvulsant properties which are useful in the treatment of idiopathic accident and drug-induced seizures. These compounds are also useful as adjunct therapy in the above conditions.
This invention provides compounds having the following structure: 
wherein n is 1 or 2, R1 is hydrogen, a linear or branched chain C1-C8 alkyl or a linear or branched chain C1-C8 alkoxy and R2 is hydrogen or a halogen and a pharmaceutically acceptable carrier.
This invention also provides a compound selected from the group consisting of N-acetyl-3-amino-1H-indene; N-acetyl-4-amino-1,2-dihydronaphthalene; N-formyl-3-amino-1H-indene; N-acetyl-3-amino-6-chloro-1H-indene; N-formyl-6-chloro-3-amino-1H-indene; and N-methoxycarbonyl-3-amino-1H-indene.
This invention also provides a method for treating injury or neurodamage caused by trauma, nutritive deprivation or deficiency, neurodegenerative pathology, or convulsant activity (idiopathic, drug-induced, etc.). This invention further provides a method for treating head trauma, stroke, hypoxia, anoxia, epilepsy, convulsions, seizures, or Alzheimer""s disease in a subject comprising administering to the subject a therapeutically effective amount of a compound having the structural formula: 
wherein n is 1 or 2, R1 is hydrogen, lower alkyl or lower alkoxy and R2 is hydrogen or halogen provided that where n is 1, and R1 is isobutyl, R2 cannot be H; and where n is 2, both R1 and R2 cannot be hydrogen.
This invention also provides a method of treating head trauma, stroke, hypoxia, anoxia, epilepsy, convulsions, seizures, or Alzheimer""s disease in a subject comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: N-acetyl-3-amino-1H-indene; N-acetyl-3-amino-6-chloro-1H-indene; N-formyl-3-amino-1H-indene; N-formyl-6-chloro-3-amino-1H-indene; N-methoxycarbonyl-3-amino-1H-indene; and N-acetyl-4-amino-1,2-dihydronaphthalene.
Further, this invention provides a process for preparing a composition of claim 1, comprising detailed steps A-D:
A. reacting an oxime with a 5- or 6-membered heterocyclic amine such as pyridine or imidazole, and acetic anhydride to produce a residue;
B. agitating the residue of step (a) with sodium carbonate;
C. extracting the residue of step (b) with a suitable solvent such as an ether or an ester; and
D. drying the residue of step (c) with a drying agent such as magnesium sulfate.